Prediction of Disease Progression to Upfront Pembrolizumab Monotherapy in Advanced Non-Small-Cell Lung Cancer with High PD-L1 Expression Using Baseline CT Disease Quantification and Smoking Pack Years

Abstract

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up CT. Associations between the baseline variables and progressive disease (PD) were tested by logistic regression analyses. The results showed 46/138 patients had PD. The baseline CT "number of involved organs" by metastasis and smoking pack years were independently associated with PD (p < 0.05), and the ROC analysis showed a good performance of the model that integrated these variables in predicting PD (AUC: 0.79). This pilot study suggests that the combination of baseline CT disease and smoking PY can identify who may progress on pembrolizumab monotherapy and can potentially facilitate decision-making for the optimal first-line treatment in the high PD-L1 cohort.

Keywords: PDL1; baseline CT; non-small-cell lung cancer; pembrolizumab; smoking pack years; survival; tumor response.

Figure 1

Performance of the MV logistical regression model (AUC at 0.79, 95% CI: 0.71–0.87). The Youden cut-off on the ROC curve was 0.20, and the “topleft” cut-off on the ROC was 0.33.

Figure 2

An example of a patient who had PD with pembrolizumab monotherapy and had a high value for the predicted risk of progression (0.93) using the prediction equation and the Youden cut-off. A 64-year-old male, current smoker, with 30 pack years, ECOG 2, diagnosed as stage IV NSCLC (adeno.). The baseline CT (A–D) showed (A) a 3.5 cm left lower lobe (LLL) primary lung mass, (B) a 2.2 cm LLL lobar adenopathy (also at the hilum and mediastinum, now shown), metastasis in the left adrenal and spleen (long and short arrows in (C)), and brain (D). After 3 months on pembrolizumab, the patient developed progressive disease on the 1st FU CT (E–H), including enlarging the LLL mass (6.1 cm, (E)), lobar adenopathy (3.2 cm, (F)), enlarging and new metastasis in the left adrenal and spleen (G), and worsening destructive bone metastases (H). The brain metastasis was radiated and improved. The patient died 7 weeks after the FU CT.

Figure 3

An example of a patient who had PR with pembrolizumab monotherapy and had a low value for the predicted risk of progression (0.03) using the prediction equation and the Youden cut-off. A 79-year-old female, ex-smoker, with 45 pack years, ECOG 1, diagnosed as stage IIIC NSCLC (adeno.). (A) The baseline CT showed a 6.0 (T3) right upper lobe primary lung tumor and 1.8 cm short axis subcarinal adenopathy (T3N2, short and long arrows in (A)), while (B) PETCT showed contralateral hilar and mediastinal adenopathy suggestive of N3 (short and long arrows in (B)). (C) The 1st FU CT after 11.5 weeks on pembrolizumab showed a partial response (PR) (RUL tumor decreased to 3.2 cm and LN decreased to a 0.7 cm short axis), and (D) the 2nd FU CT after 28 weeks showed a stable disease. The patient showed early signs of disease progression on the CT after 54 weeks on pembrolizumab.

Figure 4

The Kaplan–Meier plots comparing PFS for the predicted low- and high-risk of progression groups. The two predicted risk of progression groups were defined using the Youden cut-off (a) and the “topleft” cut-off (b). The high-risk of progression group had statistically worse PFS using both Youden and “topleft” cut-offs, while the separation of the curves between the two groups was more drastic when the groups were defined using the Youden cut-off compared to using the “topleft” cut-off (p = 0.01 and 0.03, respectively).

Figure 5

The Kaplan–Meier plots comparing OS for the predicted low- and high-risk of progression groups. The two predicted risk of progression groups were defined using the Youden cut-off (a) and the “topleft” cut-off (b). The high-risk of progression group had statistically worse OS using both Youden and “topleft” cut-offs, while the separation of the curves between the two groups was more drastic when the groups were defined using the Youden cut-off compared to using the “topleft” cut-off (both p < 0.001).